CN104418683A - Racemization method for alpha-chiral carboxylic acid - Google Patents
Racemization method for alpha-chiral carboxylic acid Download PDFInfo
- Publication number
- CN104418683A CN104418683A CN201310403447.9A CN201310403447A CN104418683A CN 104418683 A CN104418683 A CN 104418683A CN 201310403447 A CN201310403447 A CN 201310403447A CN 104418683 A CN104418683 A CN 104418683A
- Authority
- CN
- China
- Prior art keywords
- racemization
- alpha
- carboxylic acid
- chiral carboxylic
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a racemization method for alpha-chiral carboxylic acid; the method comprises the following steps: enabling alpha-chiral carboxylic acid with an optical activity, water and alkali to contact at 108-140 DEG C and under 0.11-0.5MPa, and reacting for 1-5hr to obtain a racemic product with racemization yield higher than 95%. The racemization method adopted by the invention is carried out under high pressure, and is fast in temperature rising and low in alkali consumption; the racemization method not only avoids shortcomings of a conventional process which is long in duration and high in energy consumption caused by temperature rising by virtue of water evaporating and concentrating, but also reduces alkali consumption for racemization; and corrosion of a high-alkalinity material mixing solution on racemization reaction equipment is avoided.
Description
Technical field
The present invention relates to a kind of racemization method of alpha-chiral carboxylic acid.
Background technology
Alpha-chiral carboxylic acid refers to that alpha-position carbon atom is the alkyl or aryl carboxylic acid of chiral carbon atom, and the physics and chemistry special due to it and physiological property, have extensive use in biomedicine field.In use, two kinds of enantiomers of alpha-chiral carboxylic acid often show different physiological functions.Such as conventional non-steroid antiinflammatory drug 6-methoxy-alpha-methyl-2-naphthylacetic acid.Pharmacological evaluation shows, the physiologically active of its S type enantiomorph is 27.5 times of R enantiomorph, and being therefore applied to clinical is the S type isomer of this medicine.Except the difference of physiologically active, often also there is difference in the toxic side effect of two kinds of enantiomers.As having potential acylation reaction between the acyl glucose aldehydic acid metabolite of Alpha-Methyl-3-benzoylphenylacetic acids and protein; easily bring out the selective toxicity of Immune Sensibility and tissue; and its S type enantiomorph is because eliminating the acyl glucose aldehydic acid of R type enantiomorph thus reducing the quantity of this active metabolite, alleviate the liver kidney burden of patient.Other uses the medicine of its racemic modification originally, and as 2-(4-isobutylphenyl) propionic acid, the physiologically active of its two kinds of enantiomorphs also exists significant difference, therefore there is demand alpha-chiral carboxylic acid being become single anomeric product.
In industrial production, the preparation of the alpha-chiral carboxylic acid of single configuration comprises two committed steps, namely splits and racemization.General process is racemic modification after once splitting, the material that remaining unwanted enantiomers is excessive, then through racemization, again carries out fractionation as raw material and feed intake, and so circulation makes raw material be fully utilized.Therefore the rate of recovery of the racemization operative relationship in industrial production to raw material and the quality of single anomeric product, to production cost important.Traditional Racemic of N is by the filtrate (be mainly desired product enantiomorph and a small amount of product low concentration salt solution) after splitting, and contacts with a large amount of alkali.Described alkali is generally sodium hydroxide or potassium hydroxide, and in production, total alkali charge is more than 4 times of amount of substance of the material after splitting.Experiment shows, the influence factor of alpha-chiral carboxylic acid generation racemization most critical is temperature.Even if under high concentration alkali exists, as do not reached certain temperature, racemization also can not occur.Aborning, lower owing to splitting material concentration in filtrate, about 15-20 % by weight, directly heat up after adding alkali and cannot reach racemization temperature, after must boiling off large water gaging from system, it is temperature required that temperature just can rise to racemization.The such as industrial production of S-6-methoxy-alpha-methyl-2-naphthylacetic acid, its racemization process drops into required alkali in fractionation filtrate, and reconcentration boils off the water of about 80%, when system temperature is raised to 115 ~ 130 DEG C, insulation more than 6h, thus complete racemization.The main drawback of this Racemic of N is: one, steam water concentration time long, energy consumption is large; Two, by product is many, and racemization yield is low; Three, alkali charge is comparatively large, and the alkali concn in racemization system is higher, and material has severe corrosive to equipment and operates dangerous; Four, the racemization cycle is long, increases production cost.
Summary of the invention
The object of the invention is to overcome that the racemization alkali existed in the Racemic of N of existing alpha-chiral carboxylic acid is many, enrichment step energy consumption is large and the defects such as length consuming time, providing a kind of alkali few and without the need to enrichment step thus the racemization method of the low alpha-chiral carboxylic acid of energy consumption.
To achieve these goals, the invention provides a kind of racemization method of alpha-chiral carboxylic acid, wherein, the method comprise by active for band alpha-chiral carboxylic acid, water and alkali temperature be 108 ~ 140 DEG C, pressure contacts under being 0.11 ~ 0.5MPa.
The racemization method of alpha-chiral carboxylic acid provided by the invention, reacts, makes reaction system can be warming up to higher temperature in the short period of time under adopting condition of high voltage, can save thus and steam water enrichment step, save energy consumption; And racemization with this understanding, can reduce the consumption of alkali, reduce in reaction process by the corrosion of alkali to equipment thus.
Embodiment
Below the specific embodiment of the present invention is described in detail.Should be understood that, embodiment described herein, only for instruction and explanation of the present invention, is not limited to the present invention.
The invention provides a kind of racemization method of alpha-chiral carboxylic acid, wherein, the method comprise by active for band alpha-chiral carboxylic acid, water and alkali temperature be 108 ~ 140 DEG C, pressure contacts under being 0.11 ~ 0.5MPa.
According to racemization method of the present invention, although as long as the temperature controlling contact be 108 ~ 140 DEG C, pressure is that 0.11 ~ 0.5MPa can realize goal of the invention of the present invention, under preferable case, described temperature is 110 ~ 120 DEG C.Under preferable case, described pressure is 0.15 ~ 0.4MPa.
According to racemization method of the present invention, due to described contact temperature be 108 ~ 140 DEG C, pressure carries out under being 0.11 ~ 0.5MPa, therefore compared with prior art, the duration of contact of racemization method of the present invention can obviously shorten.Under preferable case, the time of described contact is 1 ~ 5 hour, is more preferably 2 ~ 4 hours.
According to racemization method of the present invention, due to described contact temperature be 108 ~ 140 DEG C, pressure carries out under being 0.11 ~ 0.5MPa, therefore compared with prior art, the consumption of the alkali of racemization method of the present invention can obviously reduce.Under preferable case, the consumption of described alkali is 1.1 ~ 3 times of the amount of substance of described alpha-chiral carboxylic acid, is more preferably 1.5 ~ 2 times.
According to racemization method of the present invention, described alkali can be the various alkali that can be used in racemization well known in the art, and can be mineral alkali, also can be organic bases, can be highly basic, also can be weak base.Under preferable case, described alkali is one or more in lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and ammoniacal liquor.
According to racemization method of the present invention, the consumption of described water is not particularly limited, as long as can make alpha-chiral carboxylic acid and the alkali dissolution for the treatment of racemization, formation solution, under preferable case, the consumption of described water is 3 ~ 10 times of the quality of described alpha-chiral carboxylic acid, is more preferably 4 ~ 8 times.
Racemization method of the present invention may be used for the racemization of various alpha-chiral carboxylic acid, such as may be used for 2-Methyl Butyric Acid, 2-phenylpropionic acid, 6-methoxy-alpha-methyl-2-naphthylacetic acid, 2-(3-fluorine xenyl) propionic acid, 2, 3-acid dimethyl, 2 methyl valeric acid, 2-ethylpentanoic, valproic acid, 2 methyl caproic acid, 2 ethyl hexanoic acid, 2-methyl enanthic acid, 2-methyloctanoic acid, 2-ethyl is sad, 2-propyloctanoic acid, 2-butyl is sad, 2-methyl nonanoic acid, 2-phenylpropionic acid, 2-benzenebutanoic acid, α-sec.-propyl-4-chlorobenzene acetic acid, 2-(4-isobutylphenyl) propionic acid, Alpha-Methyl-3-benzoylphenylacetic acids, the racemization of one or more acid in Alpha-Methyl-3-phenoxy group toluylic acid and 2-[4-(2-Thenoyl) phenyl]-propionic acid.Under further preferable case, to treat that the gross weight of the alpha-chiral carboxylic acid of the band opticity of racemization is for 100%, wherein the difference of the weight percent of R type and S type is preferably greater than 5%, more preferably greater than 10%.In the present invention, what the difference of the weight percent of R type and S type represented is, to treat that the weight of the alpha-chiral carboxylic acid of the band opticity of racemization is for 100%, difference shared by R type between weight percent and the shared weight percent of S type, both can be the value of the weight percent of the weight percent-S type of R type, also can be the value of the weight percent of the weight percent-R type of S type.
The contact procedure of racemization method of the present invention can be carried out in the reactor of Racemic of N various being applicable to, such as, can carry out in autoclave.
In order to obtain the alpha-chiral carboxylic acid after racemization, described racemization method also comprises the mixture after by contact in the preferred case and carries out acidifying, is preferably acidified to pH1 ~ 3.Acidifying can use organic acid, also can use mineral acid, preferably uses hydrochloric acid to carry out acidifying.
According to racemization method of the present invention, under preferable case, the method can also comprise the mixture after by contact and carry out purifying.Purification process can use ordinary method well known in the art, and the present invention is special requirement not.Underpressure distillation such as can be used to carry out purifying, activated carbon decolorizing also can be used to carry out purifying.Described decolouring is preferably carried out under pH is 7-8 condition.Can regulating to obtain above-mentioned pH value by using organic acid or mineral acid, preferably using hydrochloric acid to regulate.
Below will be described the present invention by embodiment.
In the examples below, content refer to the peak area of the alpha-chiral carboxylic acid of the target product obtained by efficient liquid phase chromatographic analysis and other assorted peak-to-peak areas and per-cent.Racemization yield refers to the per-cent of the quality of the alpha-chiral carboxylic acid of the quality of (±) alpha-chiral carboxylic acid and the band opticity of input.
Embodiment 1
The present embodiment is for illustration of the racemization method of alpha-chiral carboxylic acid provided by the invention.
R-6-methoxy-alpha-methyl-2-the naphthylacetic acid of 50g is dropped in autoclave, adds 500ml water, under stirring, add the NaOH aqueous solution that 43g concentration is 30 % by weight.Build kettle cover, stir and be warming up to 135 DEG C, boost to 0.38MPa, be incubated 2 hours.After insulation terminates, this material is transferred in there-necked flask, is warming up to 75 ± 5 DEG C, adjust pH to 7-8 with hydrochloric acid, add 1g gac, at same temperature, be incubated decolouring 30 minutes.Cross and filter gac, with hydrochloric acid tune pH to 2-3, be cooled to room temperature, filter, water washing, to neutral, is dried, and obtains (±)-6-methoxy-alpha-methyl-2-naphthylacetic acid 49.2g.Detect specific optical rotation
content is 98.7%, and racemization yield is 98.4%.
Comparative example 1
Racemization is carried out according to the R-6-methoxy-alpha-methyl-2-naphthylacetic acid of method to 50.0g of embodiment 1, unlike, racemization is carried out in the there-necked flask being connected to reflux exchanger.Result temperature within the heating-up time identical with embodiment 1 refluxes when reaching 102 DEG C.Insulation reflux at such a temperature after 2 hours, carries out the post-processing step identical with embodiment 1, obtain (±)-6-methoxy-alpha-methyl-2-naphthylacetic acid 49.5g, detect specific optical rotation
this result shows that racemization does not occur R-6-methoxy-alpha-methyl-2-naphthylacetic acid.
Comparative example 2
Racemization is carried out according to the R-6-methoxy-alpha-methyl-2-naphthylacetic acid of method to 50.0g of embodiment 1, unlike, racemization is carried out in the there-necked flask being connected to atmospheric distillation plant.Heat up and be concentrated into 20% of reaction system Central Plains liquor capacity after 3 hours, temperature rises to 118 ± 3 DEG C, mend after being incubated 6 hours at such a temperature and add water to 500ml, carry out the post-processing step identical with embodiment 1, obtain (±)-6-methoxy-alpha-methyl-2-naphthylacetic acid 48.9g, detect specific optical rotation
this result shows the racemization of R-6-methoxy-alpha-methyl-2-naphthylacetic acid generating portion, but racemization is incomplete.
Comparative example 3
Racemization is carried out according to the R-6-methoxy-alpha-methyl-2-naphthylacetic acid of method to 50.0g of embodiment 1, unlike, racemization is carried out in the there-necked flask being connected to atmospheric distillation plant, and the consumption of the aqueous solution of 30 % by weight NaOH is increased to 86g.Heat up and be concentrated into 20% of reaction system Central Plains liquor capacity after 5 hours, temperature rises to 118 ± 2 DEG C, be incubated at same temperature, tracking sampling, mend after 6 hours and add water to 500ml, carry out the post-processing step identical with embodiment 1 again, obtain (±)-6-methoxy-alpha-methyl-2-naphthylacetic acid 48.7g.Detect specific optical rotation
content is 98.3%, and racemization yield is 97.4%.
Embodiment 2
The present embodiment is for illustration of the racemization method of alpha-chiral carboxylic acid provided by the invention.
Dropped in autoclave by the R-6-methoxy-alpha-methyl-2-naphthylacetic acid of 50g, add 300ml water, the concentration adding 58g under stirring is the aqueous solution of 30 % by weight NaOH.Build kettle cover, be warming up to 115 DEG C, boost to 0.2MPa, be incubated 4 hours.Insulation terminates, and is transferred in there-necked flask, is warming up to 75 ± 5 DEG C by this material, adjusts pH to 7-8, add 1g gac, be incubated decolouring 30 minutes at same temperature with hydrochloric acid.Cross and filter gac, adjust pH to 2-3 with hydrochloric acid, be cooled to room temperature, filter, wash, dry, obtain (±)-6-methoxy-alpha-methyl-2-naphthylacetic acid 49.3g.Detect specific optical rotation
content is 98.8%, and racemization yield is 98.6%.
Embodiment 3
The present embodiment is for illustration of the racemization method of alpha-chiral carboxylic acid provided by the invention.
Dropped in autoclave by the S-2-methylbutyric of 100.0g, add 400ml water, the concentration adding 144g under stirring is the NaOH aqueous solution of 30 % by weight.Build kettle cover, stir and be warming up to 135 DEG C, boost to 0.4MPa, be incubated 5 hours.Be incubated and terminate, be transferred in there-necked flask by this material, adjust pH to 1-2 with hydrochloric acid, leave standstill, separatory removes water layer, and oil reservoir is purified through rectification under vacuum, obtains (±)-2-Methyl Butyric Acid 95.2g.Detect specific optical rotation
content is 99.2%, and racemization yield is 95.2%.
Embodiment 4
The present embodiment is for illustration of the racemization method of alpha-chiral carboxylic acid provided by the invention.
Dropped in autoclave by the R-2-phenylpropionic acid of 150.0g, add 400ml water, the concentration adding 266g under stirring is the NaOH aqueous solution of 30% weight.Build kettle cover, stir and be warming up to 110 DEG C, boost to 0.15MPa, be incubated 4 hours.Insulation terminates, and is transferred in there-necked flask, is warming up to 75 ± 5 DEG C by this material, adjusts pH to 7-8, add 1.5g gac, be incubated decolouring 30 minutes at same temperature with hydrochloric acid.Cross and filter gac, with hydrochloric acid tune pH to 2-3, be cooled to 3 ± 2 DEG C, filter, water washing, to neutral, is dried, and obtains (±)-2-phenylpropionic acid 144.9g.Detect specific optical rotation
content is 98.7%, and racemization yield is 96.6%.
Embodiment 5
The present embodiment is for illustration of the racemization method of alpha-chiral carboxylic acid provided by the invention.
S-Alpha-Methyl-3-the benzoylphenylacetic acids of 50.8g dropped in autoclave, add 500ml water, the concentration adding 56g under stirring is the KOH aqueous solution of 30 % by weight.Build kettle cover, be warming up to 125 DEG C, boost to 0.25MPa, be incubated 4 hours.Insulation terminates, and is transferred in there-necked flask, is warming up to 75 ± 5 DEG C by this material, adjusts pH to 7-8, add 1g gac, be incubated decolouring 30 minutes at same temperature with hydrochloric acid.Cross and filter gac, with hydrochloric acid tune pH to 2-3, be cooled to room temperature, filter, water washing, to neutral, is dried, and obtains (±)-Alpha-Methyl-3-benzoylphenylacetic acids 48.7g.Detect specific optical rotation
content is 98.5%, and racemization yield is 95.8%.
Embodiment 6
The present embodiment is for illustration of the racemization method of alpha-chiral carboxylic acid provided by the invention.
Dropped in autoclave by S-2-(the 3-fluorine xenyl) propionic acid of 48g, add 200ml water, the concentration adding 56g under stirring is the KOH aqueous solution of 30 % by weight.Build kettle cover, be warming up to 130 DEG C, boost to 0.35MPa, be incubated 2 hours.Insulation terminates, and is transferred in there-necked flask, is warming up to 75 ± 5 DEG C by this material, adjusts pH to 7-8, add 1g gac, be incubated decolouring 30 minutes at same temperature with hydrochloric acid.Cross and filter gac, with hydrochloric acid tune pH to 2-3, be cooled to room temperature, filter, water washing, to neutral, is dried, and obtains (±)-2-(3-fluorine xenyl) propionic acid 46.2g.Detect specific optical rotation
content is 98.7%, and racemization yield is 96.2%.
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.
It should be noted that in addition, each the concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode.In order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.
In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (10)
1. a racemization method for alpha-chiral carboxylic acid, is characterized in that, the method comprise by active for band alpha-chiral carboxylic acid, water and alkali temperature be 108 ~ 140 DEG C, pressure contacts under being 0.11 ~ 0.5MPa.
2. racemization method according to claim 1, wherein, described pressure is 0.15 ~ 0.4MPa.
3. racemization method according to claim 1, wherein, described temperature is 110 ~ 135 DEG C.
4. racemization method according to claim 1, wherein, the time of described contact is 1 ~ 5 hour.
5. racemization method according to claim 4, wherein, the time of described contact is 2 ~ 4 hours.
6. racemization method according to claim 1, wherein, the consumption of described alkali is 1.1 ~ 3 times of the amount of substance of described alpha-chiral carboxylic acid.
7. racemization method according to claim 6, wherein, the consumption of described alkali is 1.5 ~ 2 times of the amount of substance of described alpha-chiral carboxylic acid.
8. the racemization method according to claim 1,6 or 7, wherein, described alkali is one or more in lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and ammoniacal liquor.
9. racemization method according to claim 1, wherein, the consumption of described water is 2 ~ 10 times of the quality of described alpha-chiral carboxylic acid.
10. racemization method according to claim 9, wherein, the consumption of described water is 4 ~ 8 times of the quality of described alpha-chiral carboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310403447.9A CN104418683A (en) | 2013-09-06 | 2013-09-06 | Racemization method for alpha-chiral carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310403447.9A CN104418683A (en) | 2013-09-06 | 2013-09-06 | Racemization method for alpha-chiral carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104418683A true CN104418683A (en) | 2015-03-18 |
Family
ID=52968894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310403447.9A Pending CN104418683A (en) | 2013-09-06 | 2013-09-06 | Racemization method for alpha-chiral carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104418683A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5221765A (en) * | 1992-01-24 | 1993-06-22 | Ethyl Corporation | Racemization process for an optically active carboxylic acid or ester thereof |
| JP3010694B2 (en) * | 1990-07-09 | 2000-02-21 | 日産化学工業株式会社 | Racemization of 2- (3-benzoyl) phenylpropionic acid |
| CN101402561A (en) * | 2008-11-17 | 2009-04-08 | 浙江天新药业有限公司 | Racemization method for L-naproxen |
| WO2010001103A1 (en) * | 2008-06-30 | 2010-01-07 | Aesica Pharmaceuticals Limited | Process for the manufacture of racemic 2-aryl-propionic acid |
-
2013
- 2013-09-06 CN CN201310403447.9A patent/CN104418683A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3010694B2 (en) * | 1990-07-09 | 2000-02-21 | 日産化学工業株式会社 | Racemization of 2- (3-benzoyl) phenylpropionic acid |
| US5221765A (en) * | 1992-01-24 | 1993-06-22 | Ethyl Corporation | Racemization process for an optically active carboxylic acid or ester thereof |
| WO2010001103A1 (en) * | 2008-06-30 | 2010-01-07 | Aesica Pharmaceuticals Limited | Process for the manufacture of racemic 2-aryl-propionic acid |
| CN101402561A (en) * | 2008-11-17 | 2009-04-08 | 浙江天新药业有限公司 | Racemization method for L-naproxen |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101607888B (en) | Alpha-keto-leucine-calcium preparation method | |
| CN106916060B (en) | Preparation method of high-purity p-hydroxyacetophenone | |
| CN104561202A (en) | Preparation method and technological system for enzymatically synthesizing N(2)-L-alanyl-L-glutamine | |
| CN103159659A (en) | Preparation method of muscarinic receptor antagonist glycopyrronium bromide | |
| CN104311422A (en) | Preparation method of antilipemic fenofibrate | |
| CN101781220B (en) | Method for preparing (+/-)-epinephrine | |
| CN104418683A (en) | Racemization method for alpha-chiral carboxylic acid | |
| WO2018086529A1 (en) | Method for enzymatic preparation of glycerol monobutyrate | |
| CN102351790A (en) | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone | |
| CN104829422A (en) | Method for splitting D,L-menthol | |
| BR102014022963A2 (en) | Methods for preparing acrylic acid from biobased starting materials | |
| CN101928214A (en) | Method for synthesizing dexketoprofen trometamol | |
| CN101514154A (en) | Synthetic method for aliphatic alpha-calcium picrolonate | |
| CN102617374B (en) | Method for preparing betaine hydrochloride | |
| CN104418810A (en) | New synthetic route of levosimendan | |
| CN104098540B (en) | A kind of method preparing Zaltoprofen | |
| CN101696223B (en) | Synthesis method of citric acid phosphoric acid ester | |
| CN1065236C (en) | Synthesis of hydrochloride of betaine | |
| CN104557752A (en) | Synthetic method of 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione compound | |
| CN103787962A (en) | Fluroxypyr sec-octyl ester synthesizing method | |
| CN102417482A (en) | Method for synthesizing ozagrel ethyl ester or ozagrel methyl ester | |
| CN106946744B (en) | A kind of novel PTP1B enzyme inhibitor and its preparation method and application | |
| CN104478756B (en) | A kind of synthetic method of (S)-metolachlor | |
| CN105367483A (en) | Preparation method of donepezil hydrochloride | |
| CN101892283A (en) | Method for catalytically preparing optically pure (S)-(+)-2-phenylpropionic acid with Rhodococcus ruber 4.1187 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150318 |